Editorial [Hot topic: Targets of Research in the Metabolic Syndrome (Guest Editor: Lindsay Brown)]

As body weight increases, there is an increase in the risk of cardiovascular and metabolic disease at all ages. The combination of obesity, hypertension and diabetes, referred to as the metabolic syndrome, is common and causes significant morbidity and mortality throughout the world. Understanding the causes and consequences of these chronic disorders, and providing rational treatment options, may improve health and lower healthcare costs. This hot issue begins with a review by Iyer and colleagues of the marked differences between males and females in both the development and the responses to pharmacological interventions of metabolic disorders such as obesity. Since most preclinical studies on animal models of the metabolic syndrome are performed in males, they argue that a better appreciation of gender differences will allow the development of relevant gender-based therapeutic interventions for chronic obesity-related diseases. Muhlhausler & Ong continue the theme with a review on the programming of food intake and its relationship with maternal diet, especially in association with an oversupply of energy, fat and sugar. The association between the increased risk of obesity in the offspring in adulthood and maternal obesity and overnutrition is well-established. The changes induced by maternal overnutrition on the development of systems regulating appetite and food preferences, including how these systems interact to stimulate the excess consumption in the offspring that predispose to obesity, are now starting to be unravelled. Since hypertension is a key component of the metabolic syndrome, it is logical to examine the role of one of the major control mechanisms for blood pressure, the renin-angiotensin system, in the control of obesity. Mathai and co-workers discuss how angiotensin II as the major peptide hormone of this system influences important determinants of adipose tissue growth such as appetite and metabolism in adipose tissue and peripheral organs. The widespread availability of highly selective inhibitors of the renin-angiotensin system for the treatment of hypertension and heart failure may allow the definition of pleiotropic responses of these compounds on the body weight of obese patients. As the renin-angiotensin system controls blood pressure, so 5'-adenosine monophosphate-activated protein kinase (AMPK) is the cellular master-switch for control of energy homeostasis. The function of this enzyme is complex and probably involves all cells in the body, as expected for the control of energy; this complexity has been characterised in the review of Mor & Unnikrishnan. This also indicates that AMPK is a valid target for the development of new drugs and the testing of natural products for therapeutic efficacy throughout the body in the metabolic syndrome. Stearoyl-CoA desaturase catalyses the formation of monounsaturated from saturated fatty acids in the formation of the polyunsaturated fatty acids. Poudyal & Brown have evaluated the role of stearoyl-CoA desaturase as a homeostatic check-point between glucose and fatty acid metabolism in the development and progression of obesity. In obesity, stearoyl-CoA desaturase has many roles, including interacting with inflammatory responses and receptors such as the PPARs. The longer chain polyunsaturated fatty acids are present in fish oil. Abeywardena and Patten have summarised the extensive evidence for the roles of the fish oils in the different aspects of the metabolic syndrome, especially the modest reduction in blood pressure, the consistent fall in concentrations of plasma triglycerides and the improvement in endothelial function. Thus, these longchain polyunsaturated fatty acids should improve cardiometabolic health, without interacting with commonly used medications for hypertension, diabetes or obesity. Obesity is considered as a low-grade inflammatory disorder with cellular damage from the lipid inflammatory mediators. Vanden Berghe and colleagues have analyzed in molecular detail how kurarinone, a lavandulyl flavanone isolated from Sophora flavescens, suppresses nuclear factor-κB (NFκB)-driven interleukin-6 (IL6) expression and cancer cell growth. This clear demonstration of the mapping of specific molecular pathways for natural products to suppress selective inflammatory pathways may show new ways to treat metabolic syndrome and other inflammatory disorders. In summary, this hot issue provides an up-to-date account of some of the exciting areas in research particularly related to the metabolic syndrome. Both basic and clinical research will be needed to find appropriate targets for intervention in the metabolic syndrome. However, these targets are likely to be relevant in other human endocrine, metabolic and immune disorders and not unique to the metabolic syndrome.